MTBVAC, a live TB vaccine poised to initiate efficacy trials 100 years after BCG

At its 100th birthday of its first administration to a newborn, BCG has been (and continues being) an inspiration for the construction and development of hundreds of new TB vaccine candidates in the last two and a half decades. Today, 14 candidates are in clinical development inside the global TB vaccine pipeline. MTBVAC is one of these candidates. Based on a live-attenuated Mycobacterium tuberculosis clinical isolate, MTBVAC''s 25 years of vaccine discovery, construction and characterisation have followed Pasteur principles, and in the process, BCG has served as a reference gold standard for establishing the safety and protective efficacy of new TB vaccine candidates. MTBVAC, which contains the antigen repertoire of M. tuberculosis, is now poised to initiate Phase 3 efficacy trials in newborns in TB-endemic countries. BCG''s efficacy extends beyond that against TB, shown to confer heterologous non-specific immunity to other diseases and reduce all-cause mortality in the first months of life. Today, WHO recognises the importance that any new TB vaccine designed for administration at birth, should show similar non-specific benefits as BCG vía mechanisms of trained immunity and/or cross-reactivity of adaptive immune responses to other pathogens. Key recent studies provide strong support for MTBVAC''s ability of inducing trained immunity and conferring non-specific heterologous protection similar to BCG. Research on alternative delivery routes of MTBVAC, such as a clinically feasible aerosol route, could facilitate vaccine administration for long-term TB eradication programmes in the future. © 2021 The Author(s

Pulmonary but not subcutaneous vaccination confers protection to TB susceptible mice by an IL17-dependent mechanism.

Some of the most promising novel tuberculosis vaccine strategies currently under development are based on respiratory vaccination, mimicking the natural route of infection. In this work, we have compared pulmonary and subcutaneous delivery of BCG vaccine in the tuberculosis-susceptible DBA/2 mouse strain, a model in which parenterally administered BCG vaccine does not protect against tuberculosis. Our data show that intranasally but not subcutaneously administered BCG confers robust protection against pulmonary tuberculosis challenge. In addition, our results indicate that pulmonary vaccination triggers a Mycobacterium tuberculosis–specific mucosal immune response orchestrated by interleukin 17A (IL-17A). Thus, IL-17A neutralization in vivo reduces protection and abrogates M. tuberculosis–specific immunoglobulin A (IgA) secretion to respiratory airways and lung expression of polymeric immunoglobulin receptor induced following intranasal vaccination. Together, our results demonstrate that pulmonary delivery of BCG can overcome the lack of protection observed when BCG is given parenterally, suggesting that respiratory tuberculosis vaccines could have an advantage in tuberculosis-endemic countries, where intradermally administered BCG has inefficient effectiveness against pulmonary tuberculosis

Therapeutic efficacy of pulmonary live tuberculosis vaccines against established asthma by subverting local immune environment

Background: Substantial recent advances in the comprehension of the molecular and cellular mechanisms behind asthma have evidenced the importance of the lung immune environment for disease outcome, making modulation of local immune responses an attractive therapeutic target against this pathology. Live attenuated mycobacteria, such as the tuberculosis vaccine BCG, have been classically linked with a type 1 response, and proposed as possible modulators of the type 2 response usually associated with asthma. Methods: In this study we used different acute and chronic murine models of asthma to investigate the therapeutic efficacy of intranasal delivery of the live tuberculosis vaccines BCG and MTBVAC by regulating the lung immune environment associated with airway hyperresponsiveness (AHR). Findings: Intranasal administration of BCG, or the novel tuberculosis vaccine candidate MTBVAC, abrogated AHR-associated hallmarks, including eosinophilia and lung remodeling. This correlated with the re-polarization of allergen-induced M2 macrophages towards an M1 phenotype, as well as with the induction of a strong allergen-specific Th1 response. Importantly, vaccine treatment was effective in a scenario of established chronic asthma where a strong eosinophil infiltration was already present prior to immunization. We finally compared the nebulization efficiency of clinical formulations of MTBVAC and BCG using a standard commercial nebulizer for potential aerosol application. Interpretation: Our results demonstrate that pulmonary live tuberculosis vaccines efficiently revert established asthma in mice. These data support the further exploration of this approach as potential therapy against asthma

Fabrication of optical waveguides in RbTiOPO4 single crystals by using different techniques

M.A. Butt, M.C. Pujol, R. Solé, A. Ródenas, G. Lifante, M. Aguiló, F. Díaz, S. N. Khonina, R. V. Skidanov and Payal Verma, "Fabrication of optical waveguides in RbTiOPO4 single crystals by using different techniques", XIII International Scientific and Technical Conference on Optical Technologies in Telecommunications,SPIE 9807 (26 March, 2016): doi: 10.1117/12.2231368. One print or electronic copy may be made for personal use only. Systematic reproduction and distribution, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper are prohibitedProceedings of XIII International Scientific and Technical Conference on Optical Technologies in Telecommunications Conference (Ufa, Russian Federation)In this work, we have demonstrated the use of different technologies to fabricate straight channel waveguides, S-bend waveguides, Y-splitter and Mach -Zehnder (MZ) structures on RbTiOPO 4 crystals and its isomorphs. We used reactive ion etching (RIE), inductively coupled plasma-RIE (ICP-RIE), femtosecond pulse laser micro-fabrication and ion diffusion techniques to structure these crystals. Computer simulations have been carried out and compared with the optical characterization of the waveguides which are in agreement with each other.This work is supported by the Ministry of Education and Science of the Russian Federation, Russian Science Foundation (grant No. 14-19-00114), Spanish Government under Projects MAT2011-29255-C02-02, TEC2014-55948-R, MAT2013-47395, C4-4-R/1-R and by the Catalan Authority under Project 2014SGR135

State-space modelling for heater induced thermal effects on LISA pathfinder's test masses

The OSE (Offline Simulations Environment) simulator of the LPF (LISA Pathfinder) mission is intended to simulate the different experiments to be carried out in flight. Amongst these, the thermal diagnostics experiments are intended to relate thermal disturbances and interferometer readouts, thereby allowing the subtraction of thermally induced interferences from the interferometer channels. In this paper we report on the modelling of these simulated experiments, including the parametrisation of different thermal effects (radiation pressure effect, radiometer effect) that will appear in the Inertial Sensor environment of the LTP (LISA Technology Package). We report as well how these experiments are going to be implemented in the LTPDA toolbox, which is a dedicated tool for LPF data analysis that will allow full traceability and reproducibility of the analysis thanks to complete recording of the processes.Postprint (published version

Gate current analysis of AlGaN/GaN on silicon heterojunction transistors at the nanoscale

The gate leakage current of AlGaN/GaN (on silicon)high electron mobility transistor(HEMT) is investigated at the micro and nanoscale. The gate current dependence (25-310 °C) on the temperature is used to identify the potential conduction mechanisms, as trap assisted tunneling or field emission. The conductive atomic force microscopy investigation of the HEMT surface has revealed some correlation between the topography and the leakage current, which is analyzed in detail. The effect of introducing a thin dielectric in the gate is also discussed in the micro and the nanoscale

Sub-femto-g free fall for space-based gravitational wave observatories: LISA pathfinder results

We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2 ± 0.1 fm s−2/√Hz or (0.54 ± 0.01) × 10−15 g/√Hz, with g the standard gravity, for frequencies between 0.7 and 20 mHz. This value is lower than the LISA Pathfinder requirement by more than a factor 5 and within a factor 1.25 of the requirement for the LISA mission, and is compatible with Brownian noise from viscous damping due to the residual gas surrounding the test masses. Above 60 mHz the acceleration noise is dominated by interferometer displacement readout noise at a level of (34.8 ± 0.3) fm/√Hz, about 2 orders of magnitude better than requirements. At f ≤ 0.5 mHz we observe a low-frequency tail that stays below 12 fm s−2/√Hz down to 0.1 mHz. This performance would allow for a space-based gravitational wave observatory with a sensitivity close to what was originally foreseen for LISA

Sub-Femto- g Free Fall for Space-Based Gravitational Wave Observatories: LISA Pathfinder Results

We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2±0.1  fm s−2/Hz, or (0.54±0.01)×10−15  g/Hz, with g the standard gravity, for frequencies between 0.7 and 20 mHz. This value is lower than the LISA Pathfinder requirement by more than a factor 5 and within a factor 1.25 of the requirement for the LISA mission, and is compatible with Brownian noise from viscous damping due to the residual gas surrounding the test masses. Above 60 mHz the acceleration noise is dominated by interferometer displacement readout noise at a level of (34.8±0.3)  fm/Hz, about 2 orders of magnitude better than requirements. At f≤0.5  mHz we observe a low-frequency tail that stays below 12  fm s−2/Hz down to 0.1 mHz. This performance would allow for a space-based gravitational wave observatory with a sensitivity close to what was originally foreseen for LISA.CNES 1316634/CNRS 103747UnivEarthS Labex program/ANR-10-LABX-0023UnivEarthS Labex program/ANR-11-IDEX-0005-02DLRFederal Ministry for Economic Affairs and Energy/FKZ 50OQ0501Federal Ministry for Economic Affairs and Energy/FKZ 50OQ1601Agenzia Spaziale ItalianaInstituto Nazionale di Fisica NucleareAYA2010-15709 (MICINN)ESP2013-47637-P (MINECO)ESP2015-67234-P (MINECO)Fundacion General CSICSwiss Space Office (SSO)Swiss National Science FoundationUnited Kingdom Space Agency (UKSA)University of GlasgowUniversity of BirminghamImperial CollegeScottish Universities Physics Alliance (SUPA)U.S. National Aeronautics and Space Administration (NASA

Measurement of the B0_s semileptonic branching ratio to an orbitally excited D_s** state, Br(B0_s -> Ds1(2536) mu nu)

In a data sample of approximately 1.3 fb-1 collected with the D0 detector between 2002 and 2006, the orbitally excited charm state D_s1(2536) has been observed with a measured mass of 2535.7 +/- 0.6 (stat) +/- 0.5 (syst) MeV via the decay mode B0_s -> D_s1(2536) mu nu X. A first measurement is made of the branching ratio product Br(b(bar) -> D_s1(2536) mu nu X).Br(D_s1(2536)->D* K0_S). Assuming that D_s1(2536) production in semileptonic decay is entirely from B0_s, an extraction of the semileptonic branching ratio Br(B0_s -> D_s1(2536) mu nu X) is made.Comment: 7 pages, 2 figures, LaTeX, version with minor changes as accepted by Phys. Rev. Let